Adducts of 3beta-acyloxy-5,7,9(11)-pregnatrien-12,20-diones



United States Patent ADDUCTS OF 3/3-ACYLOXY-5,7,9(11)-PREGNA'IRIEN-12,20-DIONES No Drawing. Application May 22, 1953, SerialN0. 356,894

' 6 Claims. (Cl. 260'.239.55)

The present invention relates to adducts of 3fl-acyloxy-5,7,9(11)-pregnatrien-12,20-diones with certain acids, anhydrides,imides and boxylic acids, particularly with maleic anhydride, maleimide,maleic acid and esters of maleic acids, and to processes for theirproduction.

Th1s application is a continuation-in-part of our copending a licationSerial No. 184,702, filed Se t b r 1 Pp p em e hydroxyl group of thesteroid with a carboxylic acid con- 13, 1950, now U. S. Patent2,623,043, issued December 23, 1952 and of our copending applicationSerial No. 228,133 filed May 24, 1951, now abandoned, to which referenceis made also for the preparation of the startmg compounds referred to inthis specification.

The adducts of 3fl-acyloxy-5,7,9(11)-pregnatrien- 12,20-d1ones which arethe preferred embodiment of this invention are represented by thefollowing formula:

CH: CH:

in which Ac is an acyl radical of the residue of an organic carboxylicacid, especially those hydrocarbon aliphatic carboxylic acids containingfrom 1 to 8 carbon atoms, inclusive, per molecule, and A is the adductradical of an p-unsaturated carbonyl compound of the group consisting ofmaleic acid, maleic anhydride, maleimide, and dialkyl maleatescontaining from 1 to 8 carbon atoms, inclusive, in each alkyl radical.

The principal object of the present invention is to provide novelcompounds which are useful in the preparationof steroid compoundscontaining an oxygen atom at carbon atom 11 in the steroid nucleus.Another object of the present invention is to provide a process for theproduction of these new compounds. Other objects and advantages of theinvention, some of which are referred to hereinafter, will be apparentto those skilled in the art to which the invention pertains.

The compounds of the present invention are useful in the preparation ofphysiologically active steroid compounds which possess an oxygen atom inposition 11 or 12. For example, heating a3fi-acyloXy-5,7,9(l1)-pregnatriene-l2,20-diones with an amine asdescribed by Levin et .all in U. S. Patent 2,577,776, issued December11, 1951, removes the adduct group yielding a 3B-acyloxy-5,7,9(11)-pregnatriene-12,20-dione, which may be hydrogenated to give3fi-acyloxypregnane-12,20-dione. Hy.-

esters of e it-unsaturated dicar- 2,697,706 Patented Dec. 21, 1954drolysis of 3,8-acyloxypregnane-12,20-dione with sodium hydroxide andoxidation with chromic acid results in the known pregnane-3,l2,20-trione[Selye, Encyclopedia of Endocrinology, section I, volume IV, 1943, A. W.T. Franks Publishing Company, Montreal, p. 603; Hoehn and Mason, J. Am.Chem. Soc. 60, 1702 (1938); Reich stein et aL, Helv. Chim. Acta 23, 747(1940)] which, has anesthetic and luteoid properties (Selye reference);When pregnane-3,l2,20-trione is reacted with sodium borohydride, the3-ketc and 12-keto groups are reduced. Treatment of the thus-obtained3a,12-dihydroxy-pregnane-20-one with acetic anhydride yields the3a-acetate and oxidation of this compound with chromic acid produces3a-acetoxy-pregnane-12,20-dione which was converted by Gallagher (U. 8.Patent 2,447,325, columns 1 and 2) into 3u-hydroxypregnane-l1,20-dione,which can be converted to cortisone by the method of Kritchevsky,Ga9r5ng31ise and Gallagher, "I: Chem. Soc. 74, 483 (l Compounds of thepresent invention which are of particular interest are those compoundsconforming to the foregoing general formula and in which AcO representsthe radical resulting from the esterification of the taining up to andincluding 8 carbon atoms. Such acids include formic, acetic, propionic,butyric, valeric, hexanoic, heptanoic, octanoic, succinic, glutaric,cyclopena tanoic, cyclohexanoic, benzoic, toluic, and the like; thelower aliphatic acids of this group are preferred embodiments of theinvention. The acids may contain substituents such as halogen, alkyl andmethoxy radicals which are nonreactive with the reagents used in themethods described herein for the preparation of the compounds of theinvention. The adduct bridge (-A-) that is represented between the 5 and8 positions of the steroid nucleus of these compounds may be representedby the. graphic form'ulae; I

and

the first of which represents that derived from maleic anhydride. andmaleimide (in which Y is an oxygen (0) or an imino (NH) radical) whilethe second represents that derived from maleic acid and its esters. Inthis second formula R represents hydrogen or an alkyl radical. Suchalkyl radicals (R) include the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, lauryl, heptyl, octyl, cyclopentyl, cyclohexyhbenzyl andsimilarradicals, which may contain substituents such as halogen, methoxyand hydroxyl radicals, which are nonreactive with the reagents used inthe methods described herein for their preparation. While adducts ofesters of maleic acids are described herein with particular reference tothose 'of dimethyl maleate, the preferred embodiment of R in theforegoing formula is a lower-alkyl radical containing ,from 1 to 8carbon atoms, inclusiv The compounds of the present invention areusually colorless crystalline solids. Those which are adducts formedfrom e o-unsaturated acids and anhydrides are readily convertible todiester adducts by esterification with reagents such as diazoalkanes inaccordance with the method described by Wilds et al. in J. Org. Chem.13, 763 (1948). The adducts of dicarboxylic acids may be converted toadducts of the corresponding dicarboxylic acid anhydrides by heat. Theadducts of acid anhydrides may be converted to those of thecorresponding acid by hydration with water.

The starting compounds from which the compounds of the present inventionare prepared are adducts of 12-hydroxy or12-bromo-3j3-acyloxy-5,7,9(1l)-pregnatrien-20- ones with maleicanhydride and its equivalents, having the general formula:

CH: CHa

in which A and Ac have the significance hereinbefore specified and X isa bromine or hydroxyl radical. The preparation of these compounds, whichis described in detail in our copending applications Serial No. 184,702,filed September 13, 1950, now U. S. Patent 2,623,043, issued' December23, 1952, and Serial No. 228,132, filed May 24, 1951, now abandoned,consists essentially of the following (Alternative procedures are alsodescribed in our said copending application):

(1) Dehydroergosterol is converted to an adduct with maleic anhydride orthe desired equivalent of maleic anhydride [H. Honigmann, Annalen 508,89-98 (1934)].

(2) The adduct of dehydroergosterol is esterified by reaction, forexample, with benzoyl chloride, acetyl chloride or formic acid.

(3) The resulting adduct of the Sfi-acyloxydehydroergosterol is ozonizedand then reduced reduced in acid solution with zinc dust to obtain anadduct of a 3/3-acyloxybisnor-5,7,9(11)-cholatrien-22-al. (Seeapplication of Robert H. Levin, Serial No. 111,100, filed August 18,1949, now U. S. Patent 2,620,337, issued December 2, 1952, for details.)

(4) An enol ester of the resulting 3p-acyloxybisnor- 5,7,9(11)-cholatrien-22-al adduct is prepared and ozonized to the adductof a 3B-acyloxy-5,7,9(11)-pregnatrien-20- one.

(5) The resulting adduct of the 3;3-acyloxy-5,7,9(l1)-pregnatrien-ZO-one is reacted with N-bromosuccinimide or bromine toproduce an adduct of a 3fl-acyloxy-12-bromo- 5 ,7,9( 11)-pregnatrien-20-one.

(6) The adduct of the 3fi-acyloxy-12-bromo-5,7,9(11)-pregnatrien-ZO-one, on reaction with silver nitrate as described in ourcopending application Serial No. 228,131, filed May 24, 1951, nowabandoned, yields the adduct of a3fl-acyloxy-l2-hydroxy-5,7,9(11)-pregnatrien-20-one, if the 1 2-hydroxyinstead of the l2-bromo is desired as the starting compound. Othermethods for the preparation of the 12-hydroxy compound are described inour copendmg application Serial No. 228,132, filed May 24, 1951, nowabandoned.

In accordance with one of the processes of our invention, adducts of3,B-acyloxy-5,7,9(11)-pregnatrien-12,20- dlones are obtained byoxidation with chromic acid of adducts of the corresponding3/3-acyloxy-12-hydroxy- 5,7,9(l1)-pregnatrien-20-ones. The 12-hydroxyadduct is ordinarily dissolved in acetic acid and an aqueous soluk tionof chromic acid added thereto in a portionwise manner. Decomposition ofthe excess chromic acid with alcohol, dilution with water, extraction ofthe mixture with a solvent, e. g., methylene chloride, and removal ofthe solvent leaves a residue of the crude product, which can bechromatographed and recrystallized to give the pure 12- ketone adduct.

The 3 acyloxy 12-keto-5,7,9(11)-pregnatrien-20-one adducts of thisinvention can also be prepared directly from 3acyloxy-12-brorno-5,7,9(ll)-pregnatrien-20-one adducts by reaction withsilver chromate and chromic acid as disclosed in Example 3 hereinafter.The 12-bromo adduct is dissolved in a suitable solvent, e. g., acetone,and silver chromate is added thereto, followed by an aqueous solution ofchromic acid. Upon completion of the reaction, a small quantity ofmineral acid, e. g., sulfuric acid, is added and the precipitatefiltered from the solution. The filtrate is diluted with water, cooled,and the crystalline l2-keto adduct separated by filtration and purifiedby chromatography and/or recrystallization, if desired.

Example 1.Maleic anhydride adduct of 3 -acet0xy-12- ket0-5,7,9(]1-pregnatrien-20-0ne To a solution of 7.7 grams of the maleic anhydrideadduct of 3fi-acetoxy-12-hydroxy-5,7,9( 11)pregnatrien- 20-one (meltingpoint, 234-237 degrees centigrade), prepared as described in ourapplication Serial No. 228,132, filed May 24, 1951, now abandoned, in300 milliliters of acetic acid was added, dropwise and with stirring, asolution of 1.1 grams of chromic acid in 18 milliliters of water. Themixture was allowed to stand at room temperature for 2 hours, excesschromic acid then decomposed by the addition of a small amount ofalcohol, and the mixture diluted with 1100 milliliters of water.Extraction with methylene chloride yielded 7.4 grams of crude product onremoval of the solvent. The crude product was chromatographed over, acolumn of Superfiltrol-Celite (1:1) and separated into-2 fractions Onefraction, which weighed 1.32 grams, was eluted from the column withether; the second fraction, which was eluted from the column withmethanol, weighed 5.83 grams. The ethereluted fraction is believed to bea maleic anhydride adduct analogous to the dimethyl maleate adductdescribed in Example 2 hereinafter and which has a melting point of218-222 degrees centigrade, and the probable formula disclosed in thesaid example. Crystallization of the methanol-eluted fraction from analcohol-acetone mixture yielded 3.15 grams of the maleic anhydrideadduct of 3fi-acetoxy-l2-keto-5,7,9( 11)-pregnatrien-20-one, meltingpoint 222-226 degrees centigrade. Several recrystallizations frommethanol raised the melting point to 232-235 degrees centigrade.

Analysis. Calculated for C27H30Ov: C, 69.51; H, 6.48. Found: C, 69.16;H, 6.75. Ultraviolet peak at 246 millimicrons; extinction coefficient of9900.

Example 2.Dimethyl maleate adduct of Sfl-acetoxy-IZ- ket0-5,7,9(11)-pregnalrien-20-one In a manner similar to that disclosed in Example 1hereinbefore, the dimethyl maleate adduct of 3/3-acetoxy-12- hydroxy5,7,9(1l) pregnatrien-ZO-one (melting point, 205-214 degreescentigrade), prepared as described in our copending application SerialNo. 228,132, filed May 24, 1951, was converted to the dimethyl maleateadduct of 3,9-acetoxy-12-keto-5,7,9( 1 1)-pregnatrien-20-one, meltingpoint 213-215 degrees centigrade; [0:11: of +1802 degrees (chloroform).

Analysis.-Calculated for C29H3s0a: C, 67.95; H, 7.08. Found: C, 67.99;H, 7.05. Ultraviolet peak at 248 millimicrons; extinction coefiicient of12400. The crude prodnot was purified by chromatography over an aluminacolumn, using a 1:1 mixture of benzene and ether as the eluent.

A second fraction was eluted from the column with ether, and wasrecrystallized and found to melt at 218-222 degrees centigrade. Itsempirical formula was CzeHsaOs, containing one atom of oxygen and twoatoms of hydrogen more than that eluted with the benzene-ether mixture.

Analysis.-Calculated for CzsHssOs: C, 65.64; H, 7.22.

Found: C, 65.64; H, 7.16. The compound eluted with ether has theprobable structural formula:

CH: CH:

CHs

OHzOOC-CH which formula was supported by infrared studies.

Example 3.Maleic anhydride adduct 0 5,7,9 (11 -pregnatrien-12,20-di0neOne gram of the maleic anhydride adduct of 3,8-acetoxy-l2-bromo5,7,9( l1)-pregnatrien--one (prepared as described in our copending applicationSerial No. 184,702,

CHzCO 0 now U. S. Patent 2,623,043, issued December 23, 1952) wasdissolved in milliliters of acetone by warming on the steam bath. Thesolution was cooled to room temperature and 0.46 gram of silverchromate, followed by 0.35 gram of chromic acid dissolved in 6milliliters of water, was added thereto. The mixture was stirred for 2hours, 1 milliliter of 5-normal sulfuric acid added, the mixture stirredfor an additional 30 minutes and then filtered. To the filtrate wasadded 100 milliliters of water. Upon cooling, 0.753 gram of crystallinematerial, melting at 228-231 degrees centigrade, was obtained.Purification of this material by chromatography over Superfiltrol-Celite gave the pure maleic anhydride adduct of 3fl-acetoxy-S ,7,9 1 1-pregnatrien-12,20-dione.

Example 4.--Dimethyl maleate adduct of 3,3-acetoxy- 5,7,9(11)-pregnatrien-12,20-dione CH! CH:

wherein Ac has the significance hereinbefore specified. The removal ofthe maleic acid or maleic anhydride radical is effected by a pyrolysisreaction which is more fully described and claimed in our copendingapplication Serial No. 228,134, filed May 24, 1951, now Patent No.2,655,- 516, and consists essentially in heating the maleic acid ormaleic anhydride adduct of the3-acyloxy-5,7,9(11)-pregnatrien-12,20-dione in the presence of anorganic amine at a temperature of approximately 100 to approximately 225degrees centigrade, with or without the presence of an organic solvent,and thereafter isolating the product triene. It is not necessary toisolate the adducts from a reaction mixture in order to effect theremoval of the adduct radical in accordance with such pyrolysisprocesses, smce the 3p-acetoxy- (7 '6 entire reaction mixture or crudeproduct may be treated." The desired triene can be obtained in a highdegree of purity and in excellent yields.

Amines which can be used in this pyrolysis processinclude: secondaryaliphatic amines such as dimethylamine, diethylamine, dipropylamine,dibutylamine, diamylamine, dioctylamine; tertiary aliphatic amines suchas trimethylamine, triamylamine, methyldioctylamine, methyldiethylamine;secondary and tertiary cycloaliphatic amines such asN-methylcyclohexylamine, N,N- dimethylcyclohexylamine, N,Ndiethylcyclohexylamine; secondary and tertiary heterocyclic amines suchas pyr rolidine, N methylmorpholine, N ethylpyrrolidine, morpholine,piperidine, 'N-methylpiperidine, Z-methylpiperidine,1,2-dimethylpiperidine, 1,2,4-trimethylpiperidine,2,4,6-trimethylpiperidine, 1-ethyl-2,4,6-trimethylpiperidine; aromaticheterocyclic amines such as pyridine, picoline, lutidine, colidine,quinoline, quinaldine, lepidine, 3-methylquinoline; secondary andtertiary carbocyclic aromatic amines such as N-methylaniline,N-ethylaniline, N- butylaniline, N-benzylaniline, N,N-dimethylaniline,N,N- diethylaniline, N,N-dibutylaniline, N,N-dibenzylaniline,N-methyltoluidine, N,N-diethyltoluidine, N-ethylxylidine,N,N-dimethylxylidine; substituted aliphatic amines such asdiethylaminoethanol, dibutylaminoethanol, N-pyrrolidylethanol,N-piperidylethanol; substituted aromatic amines such asortho-methoxy-N,N-dimethylaniline, paraethoxy-N,N-diethylaniline,para-chloro-N,N-dimethylaniline, para-bromo-N,N-diethylaniline,para-fluoro-N,N-dibutylaniline, N,N-dimethylmesidine(N,N-dimethyl-2,4,6- trimethylaniline); secondary and tertiary aralkylamines such as methylbenzylamine, dimethylbenzylamine,propylbenzylamine, diisopropylphenethylamine,diethylphenylisopropylamine; and primary amines such as butylamine,hexylamine, octylamine, cyclohexylamine, aniline, toluidine, xylidine,and the like.

The process comprises heating the selected 3-acyloxy- 12,20-dione maleicacid or maleic anhydride adduct to a temperature between approximatelyand approximately 225 degrees centigrade, preferably between and 200degrees centigrade, in the presence of an organic amine, removing excessamine, and recovering the product triene. The time required for thereaction is usually from approximately 1 to approximately 8 hours,depending upon such factors as the particular steroid adduct beingtreated, the amine employed, and the temperature of reaction.Ordinarily, a reaction period of approximately 4 hours is entirelysatisfactory, although, at lower temperatures, a more extended periodmay be employed to advantage. The emplovment of pressure may in somecases be advantageous, although it is in most cases preferred to conductthe pyrolysis reaction at atmospheric pressure. After completion of thereaction, the pure triene product can be recovered in conventionalmanner, such as by evaporation of solvent in vacuo, redissolving theresidue in an organic solvent, e. g., methanol, diluting with water,extracting with ether, washing the solution until neutral, drying,evaporating to dryness. chromatographing over an alumina column, andrecrystallizing from an or anic sol vent. if desired.

Although the foregoing specification is directed particularly to themaleic anhvdride and dimethyl maleate adducts of3fi-acetoxy-5,7,9(l1)-pregnatrien-l2.20-diones, and methods for theirpreparation from both l2-hydroxy and 12-bromo derivatives, it is to beunderstood that this is merely by way of illustration and thatmodifications and alterations may be made therein in conventional mannerand in accordance with the principles herein set forth, and that theinvention is to be limited solely by the scope of the appended claims.

We claim:

1. An adduct of 3/3-acyloxy-5,7,9(1I)-pregnatrien-l2,- 20-having theformula:

CH: CH:

2,697,706 7 8 inwhich Ac is an acyl radical of a hydrocarbon aliphaticCH; CH; carboxylic acid containing from 1 to 8 carbon atoms, in- CHelusive, and A is the adduct radical of an law-unsaturated carbonylcompound of the group consisting of maleic acid, =0

maleic anhydride, and di-lower-alkyl maleates whose alkyl 5 radicalscontain from 1 to 8 carbon atoms, inclusive.

2. A maleic anhydride adduct of a 3B-acyloxy-5,7,9-(11)-pregnatrien-12,20-dione, wherein the acyloxy group 0 is of theformula AcO, Ac being the acyl radical of a hydrocarbon aliphaticcarboxylic acid containing up to 10 eight carbon atoms, inclusive.

3. A di-lower-alkyl maleate adduct of a 3fl-acyloxy- CH 0005,7,9(11)-pregnatrien-12,20-dione, wherein the acyloxy a group is of theformula AcO, Ac being the acyl radical of GH-COOCH a hydrocarbonaliphatic carboxylic acid containing up to 15 eight carbon atoms,inclusive,

4. The maleic anhydride adduct of 3/3-acetoXy-5,7,9-

( 1 l)-pregnatrien-12,20-dione.

5. The dimethyl maleate adduct of 36-acetoxy-5,7,9-(11)-pregnatrien-12,20-dione.

6. A dimethyl maleate adduct having the empirical formula CzsHaeOs and amelting point of approximately 218-222 degrees centigrade and thestructural formula:

No references cited.

1. AN ADDUCT OF 3B-ACYLOXY-5,7,9(11)-PREGNATIEN-12,20-HAVING THEFORMULA: